Another two bite the dust – Hospira v Genentech

The IPKat has just been perusing the meaty yet compact decision in the case of Hospira v Genentech (Hospira UK Ltd v Genentech Inc [2014] EWHC 1094 (Pat) (10 April 2014)) which came out last Thursday from Mr Justice Birss. It concerns two patents, related only in that they both concern the antibody trastuzumab, more famously known as Herceptin (RTM), which is used for the treatment of breast cancer. Other than that they are quite different, the first EP 1 210 115 being concerned with a dosage regime, and the second EP 1 308 455 with a purified composition.

EP 1 210 115
Claim 1 was as follows:

Use of the anti-ErbB2 antibody huMab4D5-8 [trastuzumab]in the manufacture of a medicament for use in a method for treating a human patient diagnosed with a breast cancer characterized by overexpression of ErbB2, said method comprising the steps of administering intravenously to the patient an initial dose of 8mg/kg of the anti-ErbB2 antibody; and administering intravenously to the patient a plurality of subsequent doses of the antibody in an amount that is 6 mg/kg, wherein the doses are separated in time from each other by three weeks.

This claimed treatment regime involves an 8mg/kg loading dose and subsequent doses of 6mg/kg on a three weekly schedule. This regimen can be summarised as 8 + 6 q3w [don't you just love those pharmacist abbreviations, says Merpel - apparently the "q" stands for "quaque", meaning "every"].

Was this not the skilled team you were looking for?

This was held to be obvious over the prior FDA-approved treatment regime of 4 + 2 q1w. The clinician, it was held, would consult with the pharmacokinetics expert and decide to go ahead with a trial of a three-weekly dosing schedule and select the claimed doses.

In the alternative, if the claim was not obvious, then the judge would have considered the patent invalid for insufficiency, because “the skilled team would not conduct a clinical trial of the claimed three weekly dosing regimen based on the information in the patent read in the light of the common general knowledge”.

EP 1 308 455
Claim 1 was as follows:

A composition for therapeutic use comprising a mixture of anti-HER2 antibody and one or more acidic variants thereof,wherein the amount of the acidic variant(s) is less than about 25%,and wherein the acidic variant(s) are predominantly deamidated variants wherein one or more asparagine residues of the anti-HER2 antibody have been deamidated,and wherein the anti-HER2 antibody is huMAb4D5-8 [trastuzumab],and wherein the deamidated variants have Asn30 in CDR1 of either or both VL regions of humMAb405-8 converted to aspartate,and a pharmaceutically acceptable carrier.

This patent was about purifying trastuzumab so that it contained mainly only one acidic variant, namely one in which the asparagine residue at the 30 position had been deaminated (hydrolysed) to aspartate, and that in an amount of less than “about 25%”, which was agreed to mean less than 24.5%. It is noteworthy that the claim was not limited to any particular method, but claimed the product as such.

This was held to lack novelty over a prior Genentech PCT application PCT/US96/12251 ("Andya") which was published as WO 97/04801. In particular a specific formulation disclosed therein, which the judge found to be enabling, in which 82% of the protein was native trastuzumab, so that the maximum level of acidic variants was 18%, was held to anticipate the claim.

The claim was also held to lack inventive step having regard to “Waterside” - prior art consisting of slides presented at a conference by Reed Harris from the Analytical Chemistry Department of Genentech. Other inventive step attacks were rejected.

Finally, for good measure, a declaration of non-infringement was granted to Hospira in relation to this patent, since the levels of acidic variants were outside the range.

The judgment records that “Both patents were opposed in the EPO. In both cases the Opposition Division has held the patent is invalid. Both are presently under appeal before the Technical Board of Appeal.” The upshot of the case is that, subject to any appeal in the UK, Hospira has cleared the way to sell generic trastuzumab after the supplementary protection certificate (SPC/GB04/015) based on the basic underlying patent held by Genentech on trastuzumab (EP 0 590 058) expires on 28th July 2014.

Another two bite the dust – Hospira v Genentech
Reviewed by Darren Smyth
on
Monday, April 14, 2014
Rating: 5

11 comments:

Anonymous
said...

On the first patent I think Birss is being a little bit harsh on the plausibility requirement. He finds the invention obvious, but then goes on to find it insufficient essentially due to plausibility reasons. I'm not sure that this is a healthy development of the plausibility case law. Let's remember that plausibility grew out EPO gene cases where function was not properly disclosed in the spec, and at the EPO it is part of inventive step analysis. Now UK judges are using it to punish the quality of the patent spec, and are viewing it as part of sufficiency/enablement and in this new transmogrified form it seems the prior art cannot help to overcome plausibility. Also we need to remember plausibility is meant to have a low bar (Conor v Angiotech), and I suspect Hoffmann would not be pleased at the way Birss is now using it.

It's not a matter of punishing the spec. One must remember this is about dosage regimens - basically multiplying the amount of each dose by 3 and reducing the frequency of administering by the same factor vs. the prior art. The matter seems to be: is the leap from the specced evidence to the claimed invention smaller or larger than the leap from the prior art?In skilled person terms - is the skilled person for insufficiency matters 'smarter' than the skilled person for inventiveness? If this were to be the case, would not the skilled person be an inventor inasmuch the designated inventors?

"Now UK judges are using it to punish the quality of the patent spec, and are viewing it as part of sufficiency/enablement and in this new transmogrified form it seems the prior art cannot help to overcome plausibility."

Birss is viewing the plausibility of the claimed invention in view of the prior art. He had already found it obvious in view of the prior art, so if it wasn't obvious in view of that same prior art then the bar for plausibility is necessarily raised.

The skilled addressee unconvinced by the prior art (making it non-obvious) would also, in Birss's view, have been unconvinced by the data in the specification (making it insufficient).

Is EPO plausibility (whether it is plausible from the spec that the problem has been solved) the same as UK plausibility (does the specification teach enough to carry out the invention)? If these 2 tests are different how does the prior art relate to each of them?

"120. The law relevant to sufficiency was addressed by the Court of Appeal in Regeneron v Genentech [2013] RPC 28 at paragraphs 95-103. The scope of the monopoly, as defined in the claims, must correspond to the technical contribution the patentee has made to the art. It must therefore be possible to make a reasonable prediction that the invention will work with substantially everything falling within the scope of the claim. Putting this another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. Therefore although proof that a medicine works for a particular therapeutic purpose is not required, the patent specification must show that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible. The effect must be plausible to a person (or team) skilled in the art reading the patent with their common general knowledge."

I like your analogy, but I think the point here is that delta1 and delta2 are not independent. Delta1 must always be < delta2. If not, then the specification has disclosed no more than the prior art, right?

Birss assessed delta2 and found it so small that the application was obvious. Delta1 would be smaller still, but it is now irrelevant and need not be considered.

However, in the imaginary scenario where delta2 is large enough to make the invention non-obvious, delta1 comes into play. It may be smaller than delta2, but in this scenario Birss considered that it would still be so big as to make the application insufficient.

If you enter the imaginary world you've changed how high the cat needs to jump. That's the nature of adopting the mantle of the skilled person. Unfortunately it's not as clear cut as deltas and metres.

I want to circle back to the first comment of the thread, and the origins of the plausibility test.

At the AIPLA Annual Meeting about 6 years ago, Chris Mercer delivered a Paper about EPO practice on evidence filed after filing the patent application. He had cases in three different areas, Art 52, Art 56 and Art 87 EPC. One of his slides was entitled "The Good, the Bad and the Ugly".

Good cases are those where the pat appln makes "it" plausible but the art doesn't.

Bad cases are those where the prior art has made "it" plausible but your appln hasn't.

Ugly cases are those where it isn't clear whether either of these is "plausible".

Just as the EPO has a common notion of "disclosed" (I speak of "directly and unambiguosly derivable") for 54, 87 and 123(2) purposes, one likes to think its notion of "plausible" is constant. But is it, or is it not? You tell me.

In response to MaxDrei, plausibility was first used by the EPO in the situation where someone was claiming a new gene and the specification referred to it having X activity, but there was no direct experimental evidence in the specification of the gene possessing the activity. This was relevant where the problem was defined as providing a gene having X activity. So the specification was sufficient because it taught how to make the gene, but whether or not the problem had been solved was not clear, and so plausibility was used to assess the spec made it 'plausible' the problem had been solved. I understood this to be different from prior art based inventive step and sufficiency. In the UK plausibility has become part of sufficiency, and I don't think it should be. Coming back to your question I don't think the EPO uses plausibility any more now that there are few human gene cases being examined. In the UK it is bandied about in a casual way as part of sufficiency, and I think brought in whenever it suits the judge to evaluate the quality of the data in a spec. The problem is the UK likes doing 'squeeze' based tests, i.e. if the spec is plausible so is the prior art, and that makes is difficult to get a feel for whether plausibility is remaining constant in every case and situation.

As reported by PatLit yesterday (see http://patlit.blogspot.co.uk/2014/09/enablement-to-use-drugs-vs-enablement.html) T1616/09 shows that the EPO is also starting to look at 'plausibility' as an enablement issue, rather than an inventive step issue.